Towards Digitally Enabled Genomic Medicine the Patient of

Towards Digitally Enabled Genomic Medicine: the Patient of The Future Invited Speaker Hacking Life TTI/Vanguard Conference San Jose, CA February 22, 2012 Dr. Larry Smarr Director, California Institute for Telecommunications and Information Technology Harry E. Gruber Professor, Dept. of Computer Science and Engineering Jacobs School of Engineering, UCSD 1 http: //lsmarr. calit 2. net

Abstract Calit 2 has, for over a decade, had a driving vision that healthcare is being transformed into digitally enabled genomic medicine. To put a more personal face on the "patient of the future, " I have been increasingly quantifying my own body over the last ten years. This involves not only non-invasive macro-variables such as weight, pulse, blood pressure, caloric intake and burn, but also invasive blood, saliva, and stool measurements. I currently track over 100 molecular and blood cell types in my blood and dozens of molecular and microbial variables in my stool. Through saliva I have 1 million single nucleotide polymorphisms (SNPs) in my human DNA. My gut microbiome is currently being genetically sequenced. I will show one can discover emerging disease states before they develop serious symptoms by graphing time series of these key variables. Also I will illustrate the power of multi-variant analysis across all these internal variables. My hope is that by "living in the future" I can be a model for understanding more clearly the new approaches that will arise in wellness and health care.

Calit 2 Has Been Had a Vision of “the Digital Transformation of Health” for a Decade • Next Step—Putting You On-Line! www. bodymedia. com – Wireless Internet Transmission – Key Metabolic and Physical Variables – Model -- Dozens of Processors and 60 Sensors / Actuators Inside of our Cars • Post-Genomic Individualized Medicine – Combine – Genetic Code – Body Data Flow – Use Powerful AI Data Mining Techniques The Content of This Slide from 2001 Larry Smarr Calit 2 Talk on Digitally Enabled Genomic Medicine

The Calit 2 Vision of Digitally Enabled Genomic Medicine is an Emerging Reality 4 July/August 2011 February 2012

From One to a Billion Data Points Defining Me: The Exponential Rise in Body Data in Just One Decade! Billion: My Full DNA, MRI/CT Images Million: My DNA SNPs, Zeo, Fit. Bit One: My Weight Hundred: My Blood Variables

I am the Digitally-Enabled “Patient of the Future”: Measuring the State of Your Body and “Tuning” It 1999 2000 Age 51 2010 Age 61 I Arrived in La Jolla in 2000 After 20 Years in the Midwest and Discovered I was Pre-Diabetic

Goal: Lose Weight by Changing What & How Much I Eat, While Increasing Aerobic and Weight Bearing Exercise is Elliptical and Walking Gradually Moving to Zone Diet and Regular Exercise 182± 4 lbs. Current Weight 178. 6 Blood Pressure 134/73 Pulse 55 Resting Pulse Lowered to 45

Wireless Monitoring Helps Drive Exercise Goals

Quantifying My Sleep Pattern Using a Zeo Surprisingly About Half My Sleep is REM! REM is Normally 20% of Sleep Mine is Between 45 -65% of Sleep An Infant Typically Has 50% REM

From Measuring Macro-Variables to Measuring Your Internal Variables www. technologyreview. com/biomedicine/39636

Where I Believe We are Headed: Predictive, Personalized, Preventive, & Participatory Medicine I am Leroy Hood’s Lab Rat! Using a “Life. Chip” Quantify ~2500 Blood Proteins, 50 Each from 50 Organs or Cell Types from a Single Drop of Blood To Create a Time Series www. newsweek. com/2009/06/26/a-doctor-s-vision-of-the-future-of-medicine. html

On-Line Blood, Stool, Urine, & Saliva Tests Are Becoming Routine 25% of All Medical Tests are Conducted Outside the Hospital Laboratory I Track Over 100 Blood Molecules Every Quarter

Goal: Change Your Cholesterol Levels to Lower LDL, Raise HDL, While Lowering Total -40% LDL -45% HDL +33% Began Statin Raising “Good” HDL Seems Most Difficult

Goal: Lower Ratio of Arachidonic Acid to EPA to Reduce Pro-Inflammatory Potential of Your Cells “Silent Inflammation” Chronically Ill American I take 6 Fish Oil Pills Per Day Average “Healthy” American Ideal Range Source: Barry Sears My Tests by www. yourfuturehealth. com My Range

Blood Tests I Do Quarterly to Annually In Addition to Lipids & Omegas • • Electrolytes – Sodium, Potassium, Calcium, Magnesium, Phosphorus, Boron, Chlorine, CO 2 • – Arsenic, Chromium, Cobalt, Copper, Iron, Manganese, Molybdenum, Selenium, Zinc • – GGTP, SGOT, SGPT, LDH, Total Direct Bilirubin, Alkaline Phosphatase • Micronutrients Blood Sugar Cycle • • Protein – Total Protein, Albumin, Globulin Cancer Screen – CEA, Total PSA, % Free PSA – CA-19 -9 Kidneys – Bun, Creatinine, Uric Acid Blood Cells – Complete Blood Cell Count – Red Blood Cell Subtypes – White Blood Cell Subtypes Cardio Risk – Complex Reactive Protein – Homocysteine Thyroid – T 3 Uptake, T 4, Free Thyroxine Index, FT 4, 2 nd Gen TSH – Glucose, Insulin, A 1 C Hemoglobin • Liver • Vitamins & Antioxidant Screen – Vit D, E; Selenium, ALA, co. Q 10, Glutathione, Total Antioxidant Fn. 15 I Track Over 100 Blood Variables Over Time

But, In Spite of My High Levels of Omega-3 s, Blood Measurements Show Chronic Inflammation hs. CRP from Blood Tests 15 x Normal Symptom: Acute Diverticulitis “Come Back When You Have a Symptom” Inflammation 5 x Normal Antibiotics hs. CRP Good Range Puzzle: CRP Stays High

CRP and LDL Cholesterol Co-Create Arterial Plaque High CRP Arterial Plaque Formation CRP > 4. 2, 5 x Risk of Future Heart Disease http: //sjog. org. au/pathology_wa/doctor_resources/clinical_articles/high_sensitivity_crp. aspx

Carotid Artery Ultrasound Reveals Artery Wall Thickness Significantly Increasing In Just Two Years Oct 31 2008 October 14, 2010 IMT Right 0. 59 to 0. 73 mm 24% Thicker IMT Left 0. 75 to 0. 84 mm 12% Thicker 18

Paradox: Anti-Inflammatory Diet, Plus Low LDL, Yet Chronic Inflammation & Plaque Increases • What Could be the Source of the Chronic Inflammation? • Started Taking Stool Samples as Well as Blood Samples Do Not Assume, Always Measure! 19

Measuring Stool and Blood Markers Revealed Episodic Inflammation Peaks of CRP and Lactoferrin Stool Tests by yourfuturehealth. com Colonoscopy December 2010 Peaks 25 -30 x Normal “Significant Inflammation of Sigmoid Colon” Colonoscopy May 2006 “Mild Inflammation of Colonic Muscosa” hs. CRP Good Range Inflammatory Psedopolyp Sigmoid Colon Lactoferrin Good Range

Latest Data Point Reveals Lactoferrin Spike to Active Crohn’s Disease (CD) Level Colonoscopy May 2011 Colonoscopy and Biopsies Support CD Diagnosis Colonoscopy May 2006 Colonoscopy December 2010 Box Shows Previous Size of Graph Typical Lactoferrin Value for Active Crohn’s

Confirming the Crohn’s Hypothesis: Finding the “Smoking Gun” with MRI Imaging Liver Transverse Colon Small Intestine I Obtained the MRI Slices From UCSD Medical Services and Converted to Interactive 3 D Working With Calit 2 Staff and Software Descending Colon Diseased Sigmoid Colon Major Kink Sigmoid Colon Threading Iliac Arteries

Exploring My Internal Organs in the Calit 2 Virtual Reality CAVE Using Desk. VOX Software Photo & Desk. VOX Software Courtesy of Jurgen Schulze, Calit 2

Autoimmune Diseases Effect 5 -8% of Americans • • • Crohn’s Disease Ulcerative Colitis Rheumatoid Arthritis Multiple Sclerosis Psoriasis Type 1 Diabetes, Ankylosing Spondylitis Lupus Erythematosus Plus Over 70 Others Despite decades of research, the etiology of Crohn's disease remains unknown. Its pathogenesis may involve a complex interplay between host genetics, immune dysfunction, and microbial or environmental factors. --The Role of Microbes in Crohn's Disease Paul B. Eckburg & David A. Relman Clin Infect Dis. 44: 256 -262 (2007) The National Institute of Allergy and Infectious Diseases (NIAID)

Single Nucleotide Polymorphisms (SNPs) Make Up About 90% of All Human Genetic Variation Person A SNPs Occur Every 100 to 300 Bases Along Human DNA Person B www. 23 andme. com Tracks One Million SNPs

I Wondered if Crohn’s is an Autoimmune Disease, Did I Have a Personal Genomic Polymorphism? From www. 23 andme. com ATG 16 L 1 Polymorphism in Interleukin-23 Receptor Gene — 80% Higher Risk of Pro-inflammatory Immune Response IRGM NOD 2 SNPs Associated with CD 2009

You Are a Super. Organism: The Human Genome Contains <1% of the Bodies Genes There are 10 Times More Bacterial Cells Than of Human Cells in Your Body http: //commonfund. nih. gov/hmp/

Except for E. Coli, My “Good” Cultured Gut Bacteria Collapsed After Antibiotics 16 = All 4 at Full Strength Antibiotics: Levaquin & Metronidaloze Values From yourfuturehealth. com stool test

My Cultured Dysbiotic Bacteria Have Been Flourishing But Most Gut Bacteria Can Not Be Cultured

Crohn’s Disease Patients Have Number of Clostridium Gut Microbe Species Reduced by Over 2/3! • My Clostridia Species Were Dropping to Low Values – Clostridia are primarily responsible for butyrate production, the main energy source for colonic epithelial wall – Clostridia provide proinflammatory cytokines inhibition in the colonic muscosa • My Butyrate Values Were Very Low – “Loss of butyrate producers observed here could upset the dialogue between host epithelial cells and resident microorganisms, hence contributing to the development of CD associated ulcerations. ” Manichanh, et al, Gut 2006; 55: 205– 211 My Clostridium Species

Next Step: Use Microarray to Measure Time Series of Microbial Diversity www. secondgenome. com “Second Genome has developed a sensitive, flexible and robust platform for the identification of microbiome-based signatures for the rapid identification of microbial gut health biomarkers. ” DNA microarray that can identify, within hours, over 50, 000 different microbes LBL’s Gary Andersen and his Phylo. Chip

Microbial Metagenomics Can Diagnose Disease States From www. 23 andme. com Mutation in Interleukin-23 Receptor Gene— 80% Higher Risk of Pro-inflammatory Immune Response SNPs Associated with CD 2009 IBD Patients Harbored, on Average, 25% Fewer Microbial Genes than the Individuals Not Suffering from IBD.

First Stage of Metagenomic Sequencing of My Gut Microbiome at J. Craig Venter Institute Gel Image of Extract from Smarr Sample-Next is Library Construction Manny Torralba, Project Lead - Human Genomic Medicine J Craig Venter Institute January 25, 2012

Publically Sharing Your Genome and Medical Records: Is it Crazy or the Future? I Have Been Accepted by PGP and Will Speak at GET 2012: My Full Genome (6 Billion Bases) Will Be Sequenced This Year www. personalgenomes. org